CN118666831A - Synthesis method of isaconazole sulfate intermediate impurity - Google Patents

Abstract

The invention relates to a synthetic method of an isaconazole sulfate intermediate impurity, which relates to the technical field of organic synthesis, and the isaconazole sulfate intermediate impurity is prepared by adding (2R, 3R) -3- (2, 5-difluorophenyl) -3-hydroxy-2-methyl-4- [1H- (1, 2, 4) -triazole-1-yl ] thiobutanamide and 2-bromo-4' -cyanoacetophenone into a solvent for reaction. The invention provides a new synthetic route of the isaconazole sulfate intermediate impurity, and prepares the isaconazole sulfate intermediate impurity with high purity and quantity meeting detection requirements, and the corresponding impurity in the isaconazole intermediate and the bulk drug can be accurately qualitative and quantitative, thereby being beneficial to improving the quality of the isaconazole bulk drug, and the impurity preparation process is simple and convenient, and the purity and the yield of the obtained impurity are high.

Description

A method for synthesizing isavuconazole sulfate intermediate impurities

Technical Field

The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing isavuconazole sulfate intermediate impurities.

Background Art

Isavuconazole is a new second-generation triazole antifungal drug that was approved for marketing in the United States in 2015 for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM). Currently, there are five azole antifungal drugs in clinical use, including fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. Although these antifungal drugs all work by inhibiting the synthesis of ergosterol in the fungal cell wall, their antibacterial spectra are different. For example, posaconazole and isavuconazole can cover Aspergillus and Mucor, while fluconazole has a relatively narrow antibacterial spectrum and does not cover Aspergillus.

Among them, isavuconazole, as a new azole antifungal drug, is different from the other azole antifungal drugs mentioned above, which basically work as prototype drugs. For isavuconazole, isavuconazonium sulfate (also known as isavuconazonium) is used clinically. It is a prodrug of isavuconazole, not the sulfate of isavuconazole. It has a good solubility (>100 mg/ml) due to its positively charged triazole ring and sarcosine group. Isavuconazole greatly improves its solubility by becoming a prodrug, avoiding the use of cyclodextrin, so there is no need to consider the nephrotoxicity caused by the accumulation of this excipient in patients with renal damage, and it also brings better bioavailability.

At present, the most common synthesis route for the synthesis of isavuconazole sulfate is shown in Figure 1. The isavuconazole sulfate API prepared by Figure 1 often contains a number of unknown impurities generated by the process, which increases the difficulty of quality control of isavuconazole API and intermediates. In the above-mentioned conventional preparation method of isavuconazole, due to the activity of the triazole group of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutyramide, side reactions are prone to occur, generating isavuconazole sulfate intermediate impurities. This isavuconazole sulfate intermediate impurity is one of the main impurities generated in the synthesis process of isavuconazole. Due to its low content in the synthesis process, it is difficult to separate and it is impossible to obtain a large amount of high-purity impurities. Therefore, there is a lack of corresponding reference substances, and it is impossible to perform qualitative and quantitative detection of the impurity in the process of synthesizing isavuconazole. At the same time, the impurities directly extracted or obtained in the prior art have low purity and small quantity, and are difficult to be completely removed under process conditions, which will affect the quality of the raw materials. Therefore, in the synthesis process of isavuconazole, it is necessary to detect and control the impurities of the isavuconazole sulfate intermediate, so as to achieve the purpose of controlling the quality of the isavuconazole raw materials.

The structural formula of the isavuconazole sulfate intermediate impurity is as follows:

.

Summary of the invention

In order to solve the problem in the prior art that isavuconazole sulfate intermediate impurities generated in the preparation of isavuconazole affect the quality control of isavuconazole raw materials and intermediates, the present invention provides a method for preparing isavuconazole sulfate intermediate impurities, which is used as a reference substance for the detection of isavuconazole raw materials and intermediates, thereby achieving the control of the purity and quality of isavuconazole raw materials.

The invention provides a method for synthesizing an isavuconazole sulfate intermediate impurity. The isavuconazole sulfate intermediate impurity is prepared by adding (2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutyramide and 2-bromo-4'-cyanoacetophenone into a solvent for reaction.

The chemical structural formula of the isavuconazole sulfate intermediate impurity is as follows:

.

Furthermore, the synthesis method comprises:

(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide and 2-bromo-4'-cyanoacetophenone are added to the solvent, the reaction temperature is maintained at 20-100° C., the reaction time is 8-48 hours, and after the reaction is completed, purification is performed to obtain the isavuconazole sulfate intermediate impurity.

Furthermore, the solvent is an alcohol solvent or an ester solvent.

Furthermore, the alcohol solvent is methanol, ethanol, isopropanol or sec-butanol; the ester solvent is ethyl acetate or isopropyl acetate.

Furthermore, the reaction temperature is 60-90°C.

Furthermore, the reaction time is 8-24h.

Furthermore, the molar ratio of the (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutyramide to the 2-bromo-4'-cyanoacetophenone is 1:1-1:4.

Furthermore, the volume ratio of the (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide to the solvent is 1:(4-8).

Furthermore, the post-purification treatment includes a crystallization treatment, and the crystallization solvent of the crystallization treatment includes at least one of a sodium hydroxide solution, a potassium hydroxide solution and water.

The above technical solution provided by the embodiment of the present invention has at least the following advantages compared with the prior art:

The embodiment of the present invention provides a new synthetic route for isavuconazole sulfate intermediate impurities, and prepares impurities with high purity (HPLC purity ≥95%) and quantity meeting the detection requirements, and can accurately qualitatively and quantitatively analyze the corresponding impurities in isavuconazole intermediates and raw materials, which is beneficial to improving the quality of isavuconazole raw materials, and the impurity preparation process is simple, and the obtained impurities have high purity and yield.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

FIG. 1 is a synthetic route diagram of isavuconazole sulfate intermediate impurities in the prior art.

FIG. 2 is a synthetic route diagram of isavuconazole sulfate intermediate impurities provided in an embodiment of the present invention.

FIG. 3 is a ¹ HNMR spectrum of the isavuconazole sulfate intermediate impurity obtained in Example 3 of the present invention.

DETAILED DESCRIPTION

In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

As shown in FIG. 2 , the present invention provides a method for preparing an isavuconazole sulfate intermediate impurity and confirms the structure of the target product, wherein (2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutyramide and 2-bromo-4′-cyanoacetophenone are added to a solvent to prepare the impurity.

In the conventional preparation method of isavuconazole, the triazole group of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide is active and prone to side reactions. This isavuconazole sulfate intermediate impurity is generated during the synthesis of isavuconazole. The impurities directly extracted or obtained from it have low purity and small quantity, and are difficult to completely remove under process conditions, which will affect the quality of the raw material. Therefore, this impurity is detected and controlled during the synthesis of isavuconazole, so as to achieve the purpose of controlling the quality of the isavuconazole raw material.

The structural formula of the isavuconazole sulfate intermediate impurity is as follows:

;

The invention uses (2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutyramide and 2-bromo-4'-cyanoacetophenone as starting materials, and obtains the product through post-reaction treatment. In the original isavuconazole intermediate synthesis path, a 2-bromo-4'-cyanoacetophenone is connected to the triazole group. The impurity purity and yield obtained by the preparation method provided by the invention are high, and the product can be used as a reference substance for detecting related substances of isavuconazole raw materials and preparations, and is used for purity and quality control of isavuconazole raw materials.

The present invention provides a method for synthesizing an isavuconazole sulfate intermediate impurity, wherein the isavuconazole sulfate intermediate impurity is an isavuconazole sulfate intermediate impurity, and the method comprises the following steps:

(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide and 2-bromo-4'-cyanoacetophenone are added to the solvent, the reaction temperature is maintained at 20-100° C., and the reaction time is 8-48 hours to obtain the isavuconazole sulfate intermediate impurity.

In some specific embodiments, the solvent is an alcohol solvent or an ester solvent.

In some specific embodiments, the alcohol solvent is methanol, ethanol, isopropanol or sec-butanol; the ester solvent is ethyl acetate or isopropyl acetate.

In some specific embodiments, the reaction temperature is preferably 60-90°C.

In some specific embodiments, the reaction time is 8-24 hours, preferably 16 hours.

In some specific embodiments, the molar ratio of the (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide to the 2-bromo-4'-cyanoacetophenone is 1:1-1:4, preferably 1:2.

In some specific embodiments, the volume ratio of the (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide to the solvent is 1:(4-8), preferably 1:4 or 1:5.

In some specific embodiments, the post-purification treatment includes a crystallization treatment, and the crystallization solvent of the crystallization treatment includes at least one of a sodium hydroxide solution, a potassium hydroxide solution and water, preferably water.

In some specific embodiments, the volume ratio of the (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide to the solvent is 1:(4-12), preferably 1:8 or 1:12.

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually measured in accordance with national standards. If there are no corresponding national standards, they are carried out in accordance with general international standards, conventional conditions, or conditions recommended by the manufacturer; the raw materials involved are directly used commercial products unless otherwise specified.

In the following examples, the compound of formula 1 is (2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1H-(1,2,4)-triazol-1-yl]thiobutanamide, the compound of formula 2 is 2-bromo-4'-cyanoacetophenone, and the compound of formula 3 is an isavuconazole sulfate intermediate impurity.

Example 1

This example provides a method for synthesizing an isavuconazole sulfate intermediate impurity, the method comprising the following steps:

Reaction: 160 ml of methanol, 40.0 g of the compound of formula 1 (128 mmol) and 60.32 g of the compound of formula 2 (256 mmol) were added to the reaction flask in sequence, the temperature was raised to reflux, the reaction temperature was maintained at 65°C and the reaction was continued for 8 hours.

Post-treatment: The reaction solution was cooled to room temperature, and 460 ml of water was added, and the mixture was kept at 25 °C for 2 h for crystallization. The mixture was filtered, and the filter cake was washed with 80 ml of water and dried at 50 °C for 8 h to obtain the compound of formula 3 (40.31 g) with a yield of 54.1%. The purity of the target product of isavuconazole sulfate intermediate impurity was 97.678%.

Example 2

This example provides a method for synthesizing an isavuconazole sulfate intermediate impurity, the synthesis method comprising the following steps:

Reaction: 100 ml of ethanol, 20.0 g of the compound of formula 1 (64 mmol) and 30.21 g of the compound of formula 2 (128 mmol) were added to the reaction flask in sequence, the temperature was raised to reflux, the reaction temperature was maintained at 78°C and the reaction was continued for 8 hours.

Post-treatment: The reaction solution was cooled to 60°C, 400 ml of water was added, and the temperature was maintained at 25°C for 16 h for crystallization. The filter cake was washed with 40 ml of water and dried at 50°C for 8 h to obtain the compound of formula 3 (26.4 g) with a yield of 71%. The purity of the target product of isavuconazole sulfate intermediate impurity was 98.461%.

Example 3

This example provides a method for synthesizing an isavuconazole sulfate intermediate impurity, the method comprising the following steps:

Reaction: 250 ml of ethanol, 60.0 g of the compound of formula 1 (192 mmol) and 90.63 g of the compound of formula 2 (404.5 mmol) were added to the reaction flask in sequence, the temperature was raised to 78°C, and the reaction was continued for 16 hours.

Post-treatment: The reaction solution was cooled to room temperature, and 500 ml of water was added, and the temperature was maintained at 25 °C for 18 h for crystallization. The filter cake was washed with 120 ml of water and dried at 50 °C for 8 h to obtain the compound of formula 3 (91.5 g) with a yield of 82%. The purity of the target product of isavuconazole sulfate intermediate impurity was 98.881%.

As shown in FIG3 , the hydrogen spectrum characterization data of the isavuconazole sulfate intermediate impurity obtained in this example are as follows:

¹ HNMR(400MHz,DMSO-d6)δ9.85(s,1H),8.81(s,1H),8.48(s,1H),8.26–8.20(m,2H),8.20–8.09(m,4H), 7.98–7.91(m,2H),7.37(ddd,J=11.1,8.9,4.5Hz,1H),7.32–7.22 (m,1H),7.12(ddd,J=9.5,6.1,3.3Hz,1H),6.61(s,1H),6.10–5.93(m,2H),5.12(d,J=14.4Hz,1H), 4.86(d,J=14.2Hz,1H), 4.20(q,J=7.2Hz,1H), 1.21(d,J=7.1Hz,3H).

Example 4

In this example, based on Example 3, a single factor variable method (i.e., only one parameter condition in Example 3 was adjusted, and the remaining steps and conditions were the same as in Example 3) was used to screen the reaction condition parameters in the preparation step of the isavuconazole sulfate intermediate impurity. The specific parameter conditions of each single variable and the yield of the obtained isavuconazole sulfate intermediate impurity are shown in Table 1.

Table 1 Screening test results of reaction condition parameters in the preparation steps of isavuconazole sulfate intermediate impurities

It can be seen from Table 1 above that the reaction condition parameters in Example 3 are the optimal condition parameters in the synthesis method of isavuconazole sulfate intermediate impurities provided by the present invention.

In summary, the embodiments of the present invention provide a new synthetic route for isavuconazole sulfate intermediate impurities, and prepare impurities with high purity (HPLC purity ≥ 95%) and quantity that meet the detection requirements, which can accurately identify and quantify the corresponding impurities in isavuconazole intermediates and raw materials, which is beneficial to improving the quality of isavuconazole raw materials, and the impurity preparation process is simple, and the obtained impurities have high purity and yield.

Various embodiments of the present invention may be presented in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity, and should not be understood as a rigid limitation on the scope of the present invention; therefore, the range description should be considered to have specifically disclosed all possible sub-ranges and single numerical values within the range. For example, the range description from 1 to 6 should be considered to have specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which apply regardless of the range. In addition, whenever a numerical range is indicated herein, it is intended to include any cited number (fractional or integer) within the indicated range.

The foregoing is merely a specific embodiment of the present invention, which enables those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features claimed herein.

Claims (9)

1. The synthesis method of the isaconazole sulfate intermediate impurity is characterized in that the isaconazole sulfate intermediate impurity is prepared by adding (2R, 3R) -3- (2, 5-difluorophenyl) -3-hydroxy-2-methyl-4- [1H- (1, 2, 4) -triazol-1-yl ] thiobutyramide and 2-bromo-4' -cyanoacetophenone into a solvent for reaction;

the chemical structural formula of the isaconazole sulfate intermediate impurity is shown as follows:

。

2. the method for synthesizing an isaconazole intermediate impurity sulfate according to claim 1, wherein said method comprises:

Adding (2R, 3R) -3- (2, 5-difluorophenyl) -3-hydroxy-2-methyl-4- [1H- (1, 2, 4) -triazol-1-yl ] thiobutyramide and 2-bromo-4' -cyanoacetophenone into a solvent, maintaining the reaction temperature at 20-100 ℃ for 8-48 hours, and carrying out purification post-treatment after the reaction is finished to obtain the isaconazole sulfate intermediate impurity.

3. The method for synthesizing an isaconazole intermediate impurity according to claim 2, wherein said solvent is an alcohol solvent or an ester solvent.

4. The method for synthesizing an isaconazole sulfate intermediate impurity according to claim 3, wherein said alcohol solvent is methanol, ethanol, isopropanol or sec-butanol; the ester solvent is ethyl acetate or isopropyl acetate.

5. The method for synthesizing an isaconazole intermediate impurity sulfate according to claim 2, wherein said reaction temperature is 60-90 ℃.

6. The method for synthesizing an isaconazole intermediate impurity sulfate according to claim 2, wherein said reaction time is 8-24 hours.

7. The method for synthesizing an isaconazole intermediate impurity according to claim 2, wherein the molar ratio of (2 r,3 r) -3- (2, 5-difluorophenyl) -3-hydroxy-2-methyl-4- [1H- (1, 2, 4) -triazol-1-yl ] thiobutanamide and 2-bromo-4' -cyanoacetophenone is 1:1-1:4.

8. The method for synthesizing an isaconazole intermediate impurity according to claim 2, wherein the volume ratio of (2 r,3 r) -3- (2, 5-difluorophenyl) -3-hydroxy-2-methyl-4- [1H- (1, 2, 4) -triazol-1-yl ] thiobutanamide and said solvent is 1 (4-8).

9. The method for synthesizing an isaconazole intermediate impurity according to claim 2, wherein said post-purification treatment comprises a crystallization treatment, and said crystallization solvent of crystallization treatment comprises at least one of sodium hydroxide solution, potassium hydroxide solution and water.